Last updated on May 2018

Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia


Brief description of study

This randomized phase III trial studies how well imatinib mesylate and combination chemotherapy work in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia. Imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving imatinib mesylate and combination chemotherapy may work better in treating patients with Philadelphia chromosome positive acute lymphoblastic leukemia.

Detailed Study Description

PRIMARY OBJECTIVES:

I. To compare disease-free survival (DFS) of standard risk pediatric Philapdelphia chromosome (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib) combined with either a high-risk Children's Oncology Group (COG)/Berlin-Frankfurt-Munster (BFM) ALL chemotherapy backbone or the more intensive European (Es)PhALL chemotherapy backbone.

SECONDARY OBJECTIVES:

I. To determine the feasibility of administration of imatinib after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk Ph+ ALL patients.

II. To determine disease-free survival (DFS) of high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib.

III. To compare rates of grade 3 or higher infections in standard risk Ph+ ALL patients between the two randomized arms.

TERTIARY OBJECTIVES:

I. To describe the toxicities associated with post-HSCT administration of imatinib.

II. To evaluate the long-term toxicities in patients treated with chemotherapy plus imatinib (no transplant), and explore the differences between arms.

III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at various time points during therapy.

IV. To determine the prognostic significance of MRD at end of Induction IA. V. To evaluate MRD during post-Induction IB therapy in standard risk (SR) patients and explore whether there are any differences between randomized arms in the proportion of patients with non-detectable MRD at each time point.

VI. To evaluate MRD in high risk (HR) patients just prior to HSCT and then at regular intervals post-HSCT and explore the association of these measurements with long-term outcome.

VII. To evaluate concordance of MRD assessments made by immunoglobulin heavy chain (IGH)-T cell receptor (TCR) polymerase chain reaction (PCR) assay and next generation sequencing (NGS) assays.

VIII. To determine prognostic significance of IKZF1 gene aberrations and deletions.

IX. To determine frequency and prognostic significance of p210 BCR-ABL1 fusion variants in pediatric Ph+ ALL.

X. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine, and methotrexate) for 6 months during the maintenance phase in standard risk Ph+ ALL patients.

XI. To identify factors associated with poor adherence. XII. To determine association between relapse risk and adherence to each oral chemotherapeutic agent (separately and combined).

XIII. To measure adherence to imatinib after allogeneic HSCT in high risk Ph+ ALL patients and identify factors associated with poor adherence.

OUTLINE

INDUCTION IA PART 1: Patients receive induction IA according to standard of care on days 1-14.

INDUCTION IA PART 2: Patients receive imatinib mesylate orally (PO) once daily (QD) on days 15-33, prednisolone PO twice daily (BID) or methylprednisolone intravenously (IV) on days 15-28, vincristine sulfate IV over 1 minute on days 15 and 22, daunorubicin hydrochloride IV over 1-15 minutes on days 15 and 22, and methotrexate intrathecally (IT) on day 29.

INDUCTION IB: Patients receive imatinib mesylate PO QD on days 1-35, cyclophosphamide IV over 30-60 minutes on days 1 and 28, mercaptopurine PO on days 1-28, cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 15-18, and 22-25, and methotrexate IT on days 8 and 22.

POST-INDUCTION THERAPY: Patients with standard risk are randomized to 1 of 2 arms. Patients with high risk are assigned to Arm C.

ARM A:

CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate PO QD on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 6, dexamethasone PO BID or IV on days 1-5, cyclophosphamide IV over 30-60 minutes on days 2-4, leucovorin calcium PO or IV on days 3 and 4, high dose cytarabine IV over 3 hours and pegaspargase IV over 1-2 hours on day 5, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate PO QD on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, dexamethasone PO BID or IV on days 1-5, vincristine sulfate IV over 1 minute on days 1 and 6, ifosfamide IV over 1 hour and mesna IV on days 2-4, leucovorin calcium PO or IV on days 3 and 4, dexrazoxane hydrochloride IV over 5-15 minutes and daunorubicin hydrochloride IV over 1-15 minutes on day 5, pegaspargase IV over 1-2 hours on day 6, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate PO QD on days 1-21, high dose cytarabine IV over 3 hours on days 1-3, dexamethasone PO BID or IV on days 1-5, etoposide IV over 1-2 hours on days 3-5, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 5, pegaspargase IV over 1-2 hours on day 6, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 1 PART 1: Patients receive imatinib mesylate PO QD on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 1 PART 2: Patients receive imatinib mesylate PO QD on days 36-63, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the absence of disease progression or unexpected toxicity.

INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD on days 1-28, methotrexate PO on days 1, 8, 15, and 22, and mercaptopurine PO on days 1-28 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 2 PART 1: Patients receive imatinib mesylate PO QD on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 2 PART 2: Patients receive imatinib mesylate PO QD on days 36-49, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the absence of disease progression or unexpected toxicity.

MAINTENANCE: Patients receive imatinib mesylate PO QD on days 1-84, methotrexate PO once weekly (QW) and IT on days 1 and 43 of courses 1, 2, and 3, and mercaptopurine PO on days 1-84. Courses with imatinib mesylate and mercaptopurine repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity.

ARM B:

INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD on days 1-63, vincristine sulfate IV over 1 minute and high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin calcium PO or IV on days 3 and 4, mercaptopurine PO on days 1-56, and methotrexate IT on days 1 and 29 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION PART 1: Patients receive imatinib mesylate PO QD on days 1-28, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 1, 8, and 15, and pegaspargase IV over 1-2 hours on day 4 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION PART 2: Patients receive imatinib mesylate PO QD on days 29-56, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine sulfate IV over 1 minute on days 43 and 50, and pegaspargase IV over 1-2 hours on day 43 in the absence of disease progression or unexpected toxicity.

INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD on days 1-56, vincristine sulfate IV over 1 minute and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours on days 2 and 22 in the absence of disease progression or unexpected toxicity.

MAINTENANCE: Patients receive imatinib mesylate PO QD on days 1-84, vincristine sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or methylprednisolone IV for course 1 and 2) on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84, methotrexate PO QW, and methotrexate IT on day 1 (and day 29 for course 1 and 2). Courses repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity.

ARM C:

CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, vincristine sulfate, dexamethasone, leucovorin calcium, high dose cytarabine, and pegaspargase as in Arm A Consolidation Block 1, and filgrastim SC on day 7 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, dexamethasone, vincristine sulfate, ifosfamide, leucovorin calcium, dexrazoxane hydrochloride, daunorubicin hydrochloride, pegaspargase, and filgrastim as Arm A Consolidation Block 2 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate, dexamethasone, etoposide, methotrexate, cytarabine, therapeutic hydrocortisone, pegaspargase, and filgrastim as in Arm A Consolidation Block 3, and high dose cytarabine IV over 3 hours on days 1-2 in the absence of disease progression or unexpected toxicity.

HSCT: Patients undergo HSCT on day 0. Patients who do not proceed to HSCT receive Delayed Intensification 1, Interim Maintenance, Delayed Intensification 2, and Maintenance as in Arm A.

POST-HSCT: Patients receive imatinib mesylate PO QD starting on days 56-365 in the in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up every year for 3 years.

Clinical Study Identifier: NCT03007147

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Jessica Boklan

Phoenix Childrens Hospital
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Arkansas Children's Hospital
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Children's Hospital Los Angeles
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Children's Hospital of Orange County
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Riley Hospital for Children
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Maine Children's Cancer Program
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Sinai Hospital of Baltimore
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Johns Hopkins University/Sidney Kimmel Cancer Center
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University of Mississippi Medical Center
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Children's Hospital and Medical Center of Omaha
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Minnie Abromowitch

University of Nebraska Medical Center
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University Medical Center of Southern Nevada
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Children's Specialty Center of Nevada II
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Sunrise Hospital and Medical Center
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Summerlin Hospital Medical Center
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Mission Hospital-Memorial Campus
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Cleveland Clinic Foundation
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The Toledo Hospital/Toledo Children's Hospital
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University of Oklahoma Health Sciences Center
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Oregon Health and Science University
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Childrens Oncology Group
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Sanford USD Medical Center - Sioux Falls
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The Children's Hospital at TriStar Centennial
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Medical City Dallas Hospital
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Children's Hospital of San Antonio
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Seattle Children's Hospital
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Providence Sacred Heart Medical Center and Children's Hospital
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Children's Hospital of Alabama
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Southern California Permanente Medical Group
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City of Hope Comprehensive Cancer Center
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Loma Linda University Medical Center
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Children's Hospital Central California
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Children's Hospital and Research Center at Oakland
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Kaiser Permanente-Oakland
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Lucile Packard Children's Hospital Stanford University
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University of California Davis Comprehensive Cancer Center
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Rady Children's Hospital - San Diego
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UCSF Medical Center-Mission Bay
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Children's Hospital Colorado
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Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
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Connecticut Children's Medical Center
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Children's National Medical Center
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Golisano Children's Hospital of Southwest Florida
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University of Florida Health Science Center - Gainesville
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Memorial Regional Hospital/Joe DiMaggio Children's Hospital
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University of Miami Miller School of Medicine-Sylvester Cancer Center
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Florida Hospital Orlando
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Arnold Palmer Hospital for Children
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Johns Hopkins All Children's Hospital
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Saint Mary's Hospital
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Kapiolani Medical Center for Women and Children
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Saint Vincent Hospital and Health Care Center
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University of Kentucky/Markey Cancer Center
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C S Mott Children's Hospital
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Helen DeVos Children's Hospital at Spectrum Health
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Bronson Methodist Hospital
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Beaumont Children's Hospital-Royal Oak
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Children's Hospitals and Clinics of Minnesota - Minneapolis
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The Childrens Mercy Hospital
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Mercy Hospital Saint Louis
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Dartmouth Hitchcock Medical Center
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Hackensack University Medical Center
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Morristown Medical Center
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Roswell Park Cancer Institute
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University of Rochester
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Stony Brook University Medical Center
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State University of New York Upstate Medical University
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UNC Lineberger Comprehensive Cancer Center
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East Carolina University
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Children's Hospital Medical Center of Akron
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Rainbow Babies and Childrens Hospital
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Nationwide Children's Hospital
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Children's Hospital of Philadelphia
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West Virginia University Healthcare
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Saint Vincent Hospital Cancer Center Green Bay
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Marshfield Clinic
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Children's Hospital of Wisconsin
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Kingston Health Sciences Centre
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